Cardiovascular Drug Development Research Articles

Practical Aspects of Using Large Language Models to Screen Abstracts for Cardiovascular Drug Development: Cross-Sectional Study.

Cardiovascular drug development requires synthesizing relevant literature about indications, mechanisms, biomarkers, and outcomes. This short study investigates the performance, cost, and prompt engineering trade-offs of 3 large language models accelerating the literature screening process for cardiovascular drug development applications.

The potential of flavonoids to mitigate cellular senescence in cardiovascular disease.

Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids.

Traditional Chinese medicine: cardiovascular drug development through a holistic framework.

Traditional Chinese medicine: cardiovascular drug development through a holistic framework.

A translational framework of genoproteomic studies for cardiovascular drug discovery

Cardiovascular drug development has faced significant challenges in recent decades. The emergence of population-scale genome- and proteome-wide data, alongside sophisticated genetic analytical tools like Mendelian randomization and pragmatic target trials, presents an unprecedented chance to identify and validate drug-targeting proteins for cardiovascular disease. However, how to translate these advances into clinical applications remains to be discovered. This study proposes and validates a translational framework that leverages emerging genoproteomic data and cutting-edge causal analysis techniques to address the intricate benefit-risk concerns associated with cardiovascular drug development. Specifically, the framework elucidates underlying biological mechanisms, identifies and validates potential drug-targeting proteins, and explores the unintended side effects, complementary with pragmatic target trials. Moreover, we illustrate the translational framework via a step-by-step example alongside practical implementation recommendations for cardiovascular drug discovery. We envision this translational framework as a starting point in advancing multi-omics studies, thereby accelerating cardiovascular drug development.

Circular RNA in Cardiovascular Diseases: Biogenesis, Function and Application.

Cardiovascular diseases pose a significant public health challenge globally, necessitating the development of effective treatments to mitigate the risk of cardiovascular diseases. Recently, circular RNAs (circRNAs), a novel class of non-coding RNAs, have been recognized for their role in cardiovascular disease. Aberrant expression of circRNAs is closely linked with changes in various cellular and pathophysiological processes within the cardiovascular system, including metabolism, proliferation, stress response, and cell death. Functionally, circRNAs serve multiple roles, such as acting as a microRNA sponge, providing scaffolds for proteins, and participating in protein translation. Owing to their unique properties, circRNAs may represent a promising biomarker for predicting disease progression and a potential target for cardiovascular drug development. This review comprehensively examines the properties, biogenesis, and potential mechanisms of circRNAs, enhancing understanding of their role in the pathophysiological processes impacting cardiovascular disease. Furthermore, the prospective clinical applications of circRNAs in the diagnosis, prognosis, and treatment of cardiovascular disease are addressed.

Advancing Cardiomyocyte Maturation: Current Strategies and Promising Conductive Polymer-Based Approaches.

Cardiovascular diseases are a leading cause of mortality and pose a significant burden on healthcare systems worldwide. Despite remarkable progress in medical research, the development of effective cardiovascular drugs has been hindered by high failure rates and escalating costs. One contributing factor is the limited availability of mature cardiomyocytes (CMs) for accurate disease modeling and drug screening. Human induced pluripotent stem cell-derived CMs offer a promising source of CMs; however, their immature phenotype presents challenges in translational applications. This review focuses on the road to achieving mature CMs by summarizing the major differences between immature and mature CMs, discussing the importance of adult-like CMs for drug discovery, highlighting the limitations of current strategies, and exploring potential solutions using electro-mechano active polymer-based scaffolds based on conductive polymers. However, critical considerations such as the trade-off between 3D systems and nutrient exchange, biocompatibility, degradation, cell adhesion, longevity, and integration into wider systems must be carefully evaluated. Continued advancements in these areas will contribute to a better understanding of cardiac diseases, improved drug discovery, and the development of personalized treatment strategies for patients with cardiovascular disorders.

Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance.

Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.

Subtype and Lineage-Mediated Protocol for Standardizing Activin/Nodal and BMP Signaling for hiPSC-Derived Cardiomyocyte Differentiation.

The adept and systematic differentiation of embryonic stem cells (ESCs) and human-induced pluripotent stem cells (hiPSCs) to diverse lineage-prone cell types involves crucial step-by-step process that mimics the vital strategic commitment phase that is usually observed during the process of embryo development. The development of precise tissue-specific cell types from these stem cells indeed plays an important role in the advancement of imminent stem cell-based therapeutic strategies. Therefore, the usage of hiPSC-derived cell types for subsequent cardiovascular disease modeling, drug screening, and therapeutic drug development undeniably entails an in-depth understanding of each and every step to proficiently stimulate these stem cells into desired cardiomyogenic lineage. Thus, to accomplish this definitive and decisive fate, it is essential to efficiently induce the mesoderm or pre-cardiac mesoderm, succeeded by the division of cells into cardiovascular and ultimately ensuing with the cardiomyogenic lineage outcome. This usually commences from the earliest phases of pluripotent cell induction. In this chapter, we discuss our robust and reproducible step-wise protocol that will describe the subtype controlled, precise lineage targeted standardization of activin/nodal, and BMP signaling molecules/cytokines, for the efficient differentiation of ventricular cardiomyocytes from hiPSCs via the embryoid body method. In addition, we also describe techniques to dissociate hiPSCs, hiPSC-derived early cardiomyocytes for mesoderm and pre-cardiac mesoderm assessment, and hiPSC-derived cardiomyocytes for early and mature markers assessment.

Bradycardic effect of endothelial-specific bradykinin type-II receptors overexpression in mice: impact on blood pressure

Abstract Background/Introduction Polymorphisms of the gene encoding for the bradykinin type-II receptors (B2R) has been shown to decrease the expression of B2R and increased vascular resistance and blood pressure in humans. Purpose We aimed to study the role of endothelial B2R on systolic blood pressure (SBP) and heart rate (HR) using a novel mice model with endothelial-specific B2R overexpression (B2tg) as compared with transgene negative littermates (B2n) and on differential expression of proteins potentially relevant to vascular tension. Methods Human and murine B2R expression levels were quantified by rtPCR. Thoracic aortic tissues were used for vascular reactivity studies and proteomic analysis. SBP and HR were measured by the tail-cuff method at baseline, after administration of the COX inhibitor diclofenac (10 mg/kg/day), B2R antagonist icatibant (1 mg/kg) or NOS inhibitor L-NAME (100 mg/kg/day). Results In aortic tissues of B2tg human B2R were exclusively expressed (n=6, P=0.0005), while murine B2R expression levels remained unchanged. Similar results were found in skeletal muscle tissues used as an estimate for resistance vessels. Aortic ring studies revealed a concentration-dependent constriction to bradykinin in wild-type mice (maximal vasoconstriction 9.6±3.0%, n=5) whereas aortic rings of B2tg showed concentration-dependent relaxation (-27.4±4.1%, n=12). SBP was significantly lower in B2tg (125.0 ±1.6 mmHg) as compared to B2n (129.9±1.1 mmHg, n=9, P=0.03). Diclofenac treatment slightly but not significantly reduced SBP in B2n (to 125.5±2.4 mmHg, P=0.09) and in B2tg (to 119.8±2.8 mmHg, n=9, P=0.12), however the difference in SBP remained (P=0.03). In a pilot study, L-NAME administration did also not change the SBP difference between B2n and B2tg (9.9±10.3 mmHg, n=3-4). In contrast, icatibant administration abolished the difference between the groups (B2n 128.6±4.6 vs B2tg 128.3±2.0 mmHg, n=8, P=ns) suggesting the involvement of endothelial B2R in SBP reduction. Interestingly, in the same mice, HR was significantly lower in B2tg (571.4±20.8 bpm) as compared to B2n (626.7±13.7 bpm, P=0.02). While diclofenac didn’t affect HR, icatibant significantly increased HR to (630.8±21.8 bpm in B2tg and 685.5±16.4 bpm in B2n, n=8, P=0.01). Only in B2tg, there was a significant strong correlation between SBP and HR (r=0.76, P=0.016). Analysis of proteomic data revealed differential upregulation of proteins related to cell adhesion (CD44), extracellular matrix (hyaluronidase), and differential downregulation of proteins related to oxidative stress (superoxide dismutase) in B2tg. Conclusion Endothelial B2R overexpression reduces SBP and HR. SBP reduction is not dependent on two major vascular pathways stimulated by products of NOS and COX but appears to be related to endothelial B2R-dependent HR reduction. Hence, agonism at B2R could be a valuable target for development of new cardiovascular drugs.

Computational screen for sex-specific drug effects in a cardiac fibroblast signaling network model

Heart disease is the leading cause of death in both men and women. Cardiac fibrosis is the uncontrolled accumulation of extracellular matrix proteins, which can exacerbate the progression of heart failure, and there are currently no drugs approved specifically to target matrix accumulation in the heart. Computational signaling network models (SNMs) can be used to facilitate discovery of novel drug targets. However, the vast majority of SNMs are not sex-specific and/or are developed and validated using data skewed towards male in vitro and in vivo samples. Biological sex is an important consideration in cardiovascular health and drug development. In this study, we integrate a cardiac fibroblast SNM with estrogen signaling pathways to create sex-specific SNMs. The sex-specific SNMs demonstrated high validation accuracy compared to in vitro experimental studies in the literature while also elucidating how estrogen signaling can modulate the effect of fibrotic cytokines via multi-pathway interactions. Further, perturbation analysis and drug screening uncovered several drug compounds predicted to generate divergent fibrotic responses in male vs. female conditions, which warrant further study in the pursuit of sex-specific treatment recommendations for cardiac fibrosis. Future model development and validation will require more generation of sex-specific data to further enhance modeling capabilities for clinically relevant sex-specific predictions of cardiac fibrosis and treatment.

Effects of Angiotensin 1-7 Binding on the Dynamics of Human MAS Proto-Oncogene, GPCR: A Molecular Dynamics Study

The understanding of the connections between Angiotensin peptides with the receptors in the Renin-angiotensin system (RAS) is not clear yet. The ACE2/Ang (1-7)/MAS axis, commonly referred to as the protective arm of the RAS, plays a crucial role in maintaining homeostasis within the cardiovascular system. Angiotensin 1-7 (Ang 1-7) is a heptapeptide an integral part of the protective arm of RAS and acts as a ligand binding to the MAS receptor. Understanding the signaling system of the ACE2/Ang (1-7)/MAS axis, which occupies an important place in the RAS, can be considered a serious putative target for the development of new cardiovascular and cancer drugs. It is very important to understand whether the Ang (1-7) ligand binds stably to MAS and, if so, how this affects the dynamics of the receptor. Therefore, we investigated how Ang (1-7) binding affects the stability and communication of the MAS receptor by utilizing molecular dynamics (MD) simulations and various computational techniques. Results indicated that Ang (1-7) was stably bonded to the MAS receptor over the 300[Formula: see text]ns simulation period. It was also observed that ligand binding caused a reduction in the fluctuations of the MAS residues. Major changes include a reduction in flexibility of the N-terminal domain, ICL1, ECL1, ECL2, ECL3, TM6 and C-terminal domain residues. Our findings presented in this study may provide a contribution to future studies seeking to gain a deeper understanding of the role of Ang (1-7) interaction with the MAS receptor in the RAS.

Nano-textured polydimethylsiloxane cantilever with embedded silver nanowire networks for drug screening applications

Drug-induced cardiotoxicity is the primary cause of heart failure and leading to withdrawal of drugs from the market. Although in vitro animal models are successfully used in fundamental research on heart physiology, cardiac disease, and cardiovascular drug development, the immature cardiomyocytes utilized in existing in vitro screening techniques cannot effectively replicate the natural physiology of adult cardiomyocytes. As a result, the results obtained in vivo contradict those obtained in vitro. Herein, we propose a nanotextured polydimethylsiloxane cantilever integrated with embedded silver nanowire (AgNWs-E-PDMS) to enhance cardiomyocyte maturation. The cardiomyocytes cultured on the functional PDMS cantilever exhibit an enhanced cell viability, synchronized and stable beating behavior, and Ca2+ transient signals and cell adhesion. The Western blot (WB) and reverse transcription polymerase chain reaction (RT-qPCR) tests also showed that connexin-43 (Cx43) protein and its gene expression in cardiomyocytes are 4.59 and 1.75 times higher than in the control group of cardiomyocytes. The performance of the cantilever-based screening platform is also verified by performing sequential drug analysis using neonatal rat ventricular myocytes (NRVM) and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) on nanotextured PDMS and AgNWs-E-PDMS cantilevers. We expect that the proposed cantilever device will help reduce the risk of drug-induced heart disease in the early stages of drug development.

Advancement of targeted protein degradation strategies as therapeutics for undruggable disease targets.

Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising results in oncological, neurogenerative, cardiovascular and gynecological drug development. We provide an overview of technology advancements in TPD, including molecular glues, proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras, antibody-based PROTAC, GlueBody PROTAC, autophagy-targeting chimera, autophagosome-tethering compound, autophagy-targeting chimera and chaperone-mediated autophagy-based degraders. Here we discuss the development and evolution of the TPD field, the variety of proteins that PROTACs target and the biological repercussions of their degradation. We particularly highlight the recent improvements in TPD research that utilize autophagy or the endolysosomal pathway, which enables the targeting of undruggable targets.

Will gazing into the single-cell multiome illuminate cardiovascular drug development?

Will gazing into the single-cell multiome illuminate cardiovascular drug development?

Selección de lo mejor del año 2022 en cardiología clínica y farmacoterapia cardiovascular

Cardiovascular diseases are the leading cause of death in western countries. Therapeutic advances with the development of cardiovascular drugs have led to great advances in the prognosis of patients with heart disease.The development of drugs that drastically reduce the low-density lipoprotein cholesterol, or antidiabetics that have become a main pillar in the treatment of heart failure, take us to a very attractive horizon in the management and control of cardiovascular risk factors and patients with heart disease.In this article we review a few recent cardiovascular drugs very useful for the clinical cardiologist, without neglecting the importance of therapeutic adherence.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Heart-on-a-chip using human iPSC-derived cardiomyocytes with an integrated vascular endothelial layer based on a culture patch as a potential platform for drug evaluation

Many strategies have been adopted to construct in vitro myocardium models, which are of great value to both drug cardiotoxicity evaluation and cardiovascular drug development. In particular, the recent rapid development of human-induced pluripotent stem cell (hiPSC) technology and the rise of the organ-on-a-chip technique have provided great potential to achieve more physiologically relevant in vitro models. However, recapitulating the key role of the vasculature endothelial layer in drug action on myocardium in the models is still challenging. In this work, we developed an openable heart-on-a-chip system using highly purified functional hiPSC-derived cardiomyocytes (hiPSC-CMs) with an integrated vascular endothelial layer based on our previously proposed culture-patch method. The purity and functionality of the differentiated hiPSC-CMs were characterized, which were applied into the lower chamber of the sandwich-structured device to form the CM layer. The integrity and cell morphology of the endothelial layer on the culture patch as well as the influence of fluid shear force were studied, which was integrated in between the upper and lower chambers. The constructed heart-on-a-chip was finally applied for drug testing. The effect of two cardiac targeting drugs (isoproterenol and E-4031) directly on the hiPSC-CMs or after penetrating through the endothelial layer under static or dynamic conditions was evaluated. The results demonstrated the significance of a vascular layer in in vitro myocardium models for drug testing, as well as the advantage and potential of the proposed platform for cardiovascular drug evaluation with more human physiological relevance.

Universal and Sensitive Drug Assessment Biosensing Platform Using Optimal Mechanical Beating Detection of Single Cardiomyocyte.

The preclinical assessment of efficacy and safety is essential for cardiovascular drug development in order to guarantee effective prevention and treatment of cardiovascular disease and avoid human health endangerment and a huge waste of resources. Rhythmic mechanical beating as one of the crucial cardiomyocyte properties has been exploited to establish a drug assessment biosensing platform. However, the conventional label-free biosensing platforms are difficult to perform high-throughput and high-resolution mechanical beating detection for a single cardiomyocyte, while label-based strategies are limited by pharmacologically adverse effects and phototoxicity. Herein, we propose a biosensing platform involving the multichannel electrode array device and the universal mechanical beating detection system. The platform can determine the optimal characteristic working frequency of different devices and dynamically interrogate the viability of multisite single cardiomyocytes to establish the optimized cell-based model for sensitive drug assessment. The subtle changes of mechanical beating signals induced by cardiovascular drugs can be detected by the platform, thereby demonstrating its high performance in pharmacological assessment. The universal and sensitive drug assessment biosensing platform is believed to be widely applied in cardiology investigating and preclinical drug screening.

Mammalian Sirtuins and Their Relevance in Vascular Calcification.

Cardiovascular diseases are a group of diseases with high morbidity and mortality that affect millions of people each year. Vascular calcification (VC) is an active process that involves the mineral deposition of calcium-phosphate complexes. VC is closely related to cardiovascular diseases, such as hypertension, heart failure, and calcific aortic stenosis, and is a type of ectopic calcification that occurs in the vessel walls. The sirtuins (silent mating-type information regulation 2; SIRTs), are a family of histone deacetylases whose function relies on nicotinamide adenine dinucleotide (NAD+). They have non-negligible functions in the regulation of energy metabolism, senescence, apoptosis, and other biological processes. Sirtuins have important effects on bone homeostasis and VC processes that share many similarities with bone formation. Sirtuins have been confirmed to deacetylate a variety of target proteins related to the occurrence and development of VC, thereby affecting the process of VC and providing new possibilities for the prevention and treatment of cardiovascular diseases. To facilitate the understanding of vascular calcification and accelerate the development of cardiovascular drugs, we reviewed and summarized recent research progress on the relationship between different types of sirtuins and VC.

Comparative bioactivity profile of phospholipids from three marine byproducts based on the zebrafish model.

Phospholipids (PLs) are important components of physiological metabolism in animals and plants, and they have been widely used in clinical treatment, cosmetics, and industry. With the development of marine resources, marine PLs rich in polyunsaturated fatty acids have attracted increasing attention. As important marine resources, shrimp heads (SH), codfish roe (CR), and squid gonads (SG) contain a high PL content. The antithrombotic, antistroke, anti-inflammatory, pro-angiogenic, and cardioprotective activities of PLs from SH, CR, and SG were evaluated and compared using the in vivo zebrafish model. The results showed that the PL extracts of SH, CR, and SG had significant biological activities, which lays a theoretical foundation for the development and utilization of PLs in marine byproducts in the future, providing a new choice for the prevention of inflammatory and cardiovascular diseases. PRACTICAL APPLICATIONS: In this experiment, phospholipids in seafood from different sources were extracted, and their biological activities were comprehensively evaluated and compared using the zebrafish model to lay a foundation for the development of cardiovascular drugs, health food, special medicinal food, and other effective components. The utilization of marine byproducts not only makes full use of resources, but it also protects the environment.